Bromocriptine Formulations

ABSTRACT

The present application describes pharmaceutical formulations of bromocriptine mesylate and methods of manufacturing and using such formulations. The formulations are useful for improving glycemic control in the treatment of type 2 diabetes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/920,123, filed Oct. 22, 2015, which is pending, which is acontinuation of U.S. application Ser. No. 14/088,269, filed Nov. 22,2013, now U.S. Pat. No. 9,192,576, which is a continuation of U.S.application Ser. No. 13/773,500, filed Feb. 21, 2013, now U.S. Pat. No.8,613,947, which is a continuation of U.S. application Ser. No.13/460,452, filed Apr. 30, 2012, now U.S. Pat. No. 8,431,155, the entirecontent of each of which is incorporated herein by reference.

TECHNICAL FIELD

This invention relates to pharmaceutical formulations and methods oftheir manufacture and use, and more particularly to formulations ofbromocriptine mesylate that are useful for treating type 2 diabetes.

BACKGROUND

Bromocriptine((5′α)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)-ergotaman-3′,6′,18-trione,CAS Registry No. 25614-03-3) is an ergot alkaloid which is a potentdopamine D2 receptor agonist. The compound has the following formula:

Solid oral dosage forms of bromocriptine are available as bromocriptinemesylate((5′α)-2-bromo-12′-hydroxy-2′-(1-methylethyl)-5′-(2-methylpropyl)-ergotaman-3′,6′,18-trionemonomethanesulfonate salt, CAS Registry No. 22260-51-1) in a tabletcontaining up to 2.5 mg bromocriptine or in capsule form containing 5 mgbromocriptine. Bromocriptine is useful in the treatment of certainhyperprolactinemia-associated dysfunctions and acromegaly, in theprevention of physiological lactation, and in the treatment ofParkinson's disease and prevention of tolerance to Levodopa therapy forParkinson's disease. In clinical trials, adverse effects includednausea, headache, dizziness, fatigue, lightheadedness, vomiting,abdominal cramps, nasal congestion, constipation, diarrhea anddrowsiness. When bromocriptine is used as described above, prolactin isreduced to low levels throughout a 24 hour period.

U.S. Pat. Nos. 5,344,832, 5,554,623 and 5,716,957 discuss a method formodifying and regulating lipid and glucose metabolism by administering adopamine agonist, e.g., bromocriptine, and/or a prolactin stimulator toreset hormonal timing in the neural centers of the brain to controlinsulin resistance, hyperinsulinemia and hyperglycemia.

U.S. Pat. Nos. 5,468,755, 5,756,513 and 5,866,584 discuss a method tomodify and regulate lipid and carbohydrate metabolism-generally toreduce obesity, insulin resistance, hyperinsulinemia and hyperglycemia,by administration of a dopamine agonist such as bromocriptine to inhibitprolactin over a limited period at a time of day to reset normalhormonal timing and control insulin resistance, hyperinsulinemia andhyperglycemia.

U.S. Pat. No. 5,679,685 discusses accelerated release bromocriptinemesylate formulations for regulating prolactin levels that are abnormalduring particular times during the day.

WO/2009/091576 discusses compositions for parenteral administrationusing dopamine agonists such as bromocriptine, that are described asbeing useful for treating metabolic-related conditions such as type 2diabetes.

CYCLOSE®, a tablet form of bromocriptine mesylate providing a 0.8 mgdose of bromocriptine, is FDA approved for once-daily administration toimprove glycemic control in adults with type 2 diabetes mellitus, at adose of 2-6 tablets (1.6 to 4.8 mg total dose).

SUMMARY

In one aspect, the present application provides an oral dosage form, forexample a tablet, which includes micronized bromocriptine mesylate andone or more excipients. The micronized bromocriptine mesylate is presentin an amount that provides a dose of at least about 0.8 mg ofbromocriptine per dosage form and has Dv90 of less than about 10 μm. Thedosage form provides a dissolution profile, when tested in USP ApparatusType 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid atabout 37° C., wherein at least about 90% of the bromocriptine mesylatehas been released at about 30 minutes.

In a further aspect, the present application provides a further methodfor the manufacture of a bromocriptine mesylate tablet. The methodincludes processing bromocriptine mesylate to reduce the averageparticle size of the bromocriptine mesylate to provide bromocriptinemesylate that has a Dv90 of less than about 20 μm and blending theprocessed bromocriptine mesylate with excipients to form a mixturewherein the bromocriptine mesylate is substantially evenly distributedin the mixture. The mixture is compressed to form a tablet. The tabletincludes bromocriptine mesylate in an amount that provides a dose of atleast about 0.8 mg of bromocriptine; and provides a dissolution profile,when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of0.1 N hydrochloric acid at about 37° C., wherein at least about 90% ofthe bromocriptine mesylate has been released at about 30 minutes.

In another aspect, the present application provides a method for themanufacture of a bromocriptine mesylate tablet. The method includesdetermining that bromocriptine mesylate has a particle size distributionequivalent to a volume-based particle size distribution with a Dv90 ofless than about 20 μm, blending the bromocriptine mesylate of determinedparticle size distribution with excipients to form a mixture wherein thebromocriptine mesylate is substantially evenly distributed in themixture. The mixture is compressed to form a tablet. The tablet includesbromocriptine mesylate in an amount that provides a dose of at leastabout 0.8 mg of bromocriptine; and provides a dissolution profile, whentested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1N hydrochloric acid at about 37° C., wherein at least about 90% of thebromocriptine mesylate has been released at about 30 minutes.

In another aspect, the present application provides a method oftreatment for improving glycemic control in a type 2 diabetes patient.The method includes administering a bromocriptine mesylate oral dosageform, for example a tablet, which includes micronized bromocriptinemesylate and one or more excipients. The micronized bromocriptinemesylate is present in an amount that provides a dose of at least about0.8 mg of bromocriptine per dosage form and has Dv90 of less than about10 μm. The dosage form provides a dissolution profile, when tested inUSP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 Nhydrochloric acid at about 37° C., wherein at least about 90% of thebromocriptine mesylate has been released at about 30 minutes.

In another aspect, the present application provides a further method oftreatment for improving glycemic control in a type 2 diabetes patient.The method includes processing bromocriptine mesylate to reduce theaverage particle size of the bromocriptine mesylate to providebromocriptine mesylate that has a Dv90 of less than about 20 μm andblending the processed bromocriptine mesylate with excipients to form amixture wherein the bromocriptine mesylate is substantially evenlydistributed in the mixture. The mixture is compressed to form a tablet.The tablet includes bromocriptine mesylate in an amount that provides adose of at least about 0.8 mg of bromocriptine; and provides adissolution profile, when tested in USP Apparatus Type 2 Paddle Methodat 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37° C., whereinat least about 90% of the bromocriptine mesylate has been released atabout 30 minutes. The tablet is provided for administration to thepatient.

In another aspect, the present application provides a further method oftreatment for improving glycemic control in a type 2 diabetes patient.The method includes determining that bromocriptine mesylate has aparticle size distribution equivalent to a volume-based particle sizedistribution with a Dv90 of less than about 20 μm, blending thebromocriptine mesylate of determined particle size distribution withexcipients to form a mixture wherein the bromocriptine mesylate issubstantially evenly distributed in the mixture. The mixture iscompressed to form a tablet. The tablet includes bromocriptine mesylatein an amount that provides a dose of at least about 0.8 mg ofbromocriptine; and provides a dissolution profile, when tested in USPApparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloricacid at about 37° C., wherein at least about 90% of the bromocriptinemesylate has been released at about 30 minutes. The tablet is providedfor administration to the patient.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages will be apparent from the description anddrawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a plot showing the correlation between release ofbromocriptine mesylate at about 30 minutes for various batches ofbromocriptine mesylate tablets and the Dv90 of the bromocriptinemesylate particles from which the batches were prepared.

FIG. 2 is a plot showing the correlation between release at about 30minutes for various batches of bromocriptine mesylate tablets and thespan of the particle size distribution of the bromocriptine mesylateparticles from which the batches were prepared.

FIG. 3A shows the volume-based particle size distribution measured for abatch of bromocriptine mesylate particles before micronization.

FIG. 3B shows the volume-based particle size distribution measured for abatch of bromocriptine mesylate particles after micronization.

FIG. 4 shows the cumulative volume-based particle size distribution fora batch of micronized bromocriptine mesylate particles compared withbatches of bromocriptine mesylate used in tablets which released about96% of the bromocriptine at about 30 minutes (as compared to batchesthat released about 78% of the bromocriptine at about 30 minutes.

FIG. 5 shows the volume-based particle size distribution measured for abatch of micronized bromocriptine mesylate particles used to manufacturebromocriptine mesylate tablets.

DETAILED DESCRIPTION

“About,” as used herein, means approximately, e.g., plus or minusapproximately ten percent of the indicated value.

“Particle,” as used herein, refers to an aggregated physical unit of acompound (e.g., bromocriptine mesylate), i.e., a piece or a grain.

“Particle size” as used herein, refers to the average linear dimensionof a particle of a compound, for example the diameter of a sphericalparticle of a compound.

“Micronization,” as used herein, refers to a process of reducing theaverage particle size of a solid material, typically to provideparticles with a particle size of a few micrometers.

“Micronized,” as used herein, refers to a material that has beensubjected to micronization.

The term “oral dosage form” refers to a drug dosage form that providesfor absorption of a substantial amount of the drug through the gastricand/or intestinal mucosa of the gastrointestinal tract.

The term “tablet” refers to an oral dosage form that comprises a mixtureof active substances and excipients, usually in powder form, pressed orcompacted from a powder into a solid dose.

“Particle size distribution” as used herein refers to the relativeproportions of particles of a compound, such as bromocriptine mesylate,having a given particle size. While the particle size of a sphericalobject can be unambiguously and quantitatively defined by its diameter,particles comprising an active pharmaceutical ingredient, such asbromocriptine mesylate for example, may be non-spherical and irregularin shape. There are several methods by which those of ordinary skill inthe art measure and express the size of non-spherical and irregularparticles, such as measuring the size of such particles using laserdiffractometry and expressing the size of such particles based onreplacing a given particle with an imaginary sphere that has one of anumber of properties of the particle. Such properties can be selectedfrom, for example, but are not limited to, the diameter of an imaginarysphere having the same volume of the particle being measured(volume-based particle size), the diameter of an imaginary sphere havingthe same weight as the particle being measured (weight-based particlesize), and the diameter of an imaginary sphere having the same surfacearea as the particle being measured (area-based particle size). Thosehaving ordinary skill in the art are familiar with such methods, and themanner in which the results of such methods are expressed, and suchmethods can be applied to the embodiments disclosed herein without undueexperimentation. The particle size distribution may be represented, forexample, graphically as a plot. A common type of plot is a cumulativeundersize plot which represents the fraction (e.g. by number, volume ormass) of particles that are smaller than the stated particle size.

The parameters Dv10, Dv50, Dv90 and Dv99 represent the particle size atthe 10%, 50%, 90% and 99% points of the cumulative volume undersizeparticle size distribution. Thus, a “Dv10” for a material represents aparticle size wherein 10% of the volume of the material consists ofparticles having a particle size equal to the Dv 10 value or smaller. A“Dv50” for a material represents a particle size wherein 50% of thevolume of the material consists of particles having a particle sizeequal to the Dv50 value or smaller. A “Dv90” for a material represents aparticle size wherein 90% of the volume of the material consists ofparticles having a particle size equal to the Dv90 value or smaller. A“Dv99” for a material represents a particle size wherein 99% of thevolume of the material consists of particles having a particle sizeequal to the Dv99 value or smaller.

The term “span” as used herein means a measure of the width of thedistribution of given particle sizes of a given compound comprising anembodiment disclosed herein. In particular, the span of a givenembodiment can be provided by measuring the size of the particles of agiven compound using a volume-based particle size distribution methodand applying the formula below, wherein Dv90, Dv10 and Dv50 are ashereinbefore defined:

${Span} = \frac{{{Dv}\; 90} - {{Dv}\; 10}}{{Dv}\; 50}$

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition (such as type 2 diabetes) ina patient, such as a mammal (particularly a human) that comprisesameliorating the disease or medical condition, i.e., eliminating orcausing regression of the disease or medical condition in a patient,suppressing the disease or medical condition, i.e., slowing or arrestingthe development of the disease or medical condition in a patient; oralleviating the symptoms of the disease or medical condition in apatient.

The present application describes improved bromocriptine mesylateformulations for improving glycemic control and treating type 2diabetes, manufacturing methods for preparing such formulations, as wellas methods of using such formulations. The formulations may containbromocriptine mesylate in an amount that provides a dose of at leastabout 0.8 mg, for example about 0.8 mg, of bromocriptine. Thebromocriptine mesylate may be present in the formulations as the solepharmaceutically active ingredient. The bromocriptine mesylateformulations may be oral dosage form, e.g., tablets. The bromocriptinemesylate may substantially evenly distributed in the tablets.

In one aspect, the present application describes that in the preparationof bromocriptine mesylate formulations for improving glycemic controland treating type 2 diabetes, it has been discovered that controllingthe size of the bromocriptine mesylate particles in the formulations mayaffect the potency and safety profile of the bromocriptine mesylate. Thepresent application therefore provides methods for manufacturingbromocriptine tablets comprising bromocriptine mesylate particles havinga controlled particle size, which provides a more consistent release ofbromocriptine mesylate from the formulation, which release allows theformulation to be therapeutically effective for treating type 2diabetes.

In some aspects, the present application provides methods for providingbromocriptine mesylate tablets with uniform content, such that thebromocriptine mesylate is uniformly distributed within an ingredientblend that is compressed to form tablets, and each tablet containssubstantially the same amount of bromocriptine mesylate and, as aresult, provides substantially the same dose of bromocriptine mesylateto the patient. This property is desirable so that bromocriptine tabletsprovide consistent efficacy, by ensuring that each tablet provides anefficacious amount of the drug, but also does not provide too high adose of the drug which may lead to side effects.

The mode of action involved in using bromocriptine to improve glycemiccontrol and treating type 2 diabetes presents challenges in developingand manufacturing formulations that are suitable for this purpose. Manydrugs work best when the pharmacological action of the drug (e.g.,blocking a receptor or inhibiting an enzyme) is maintained throughoutthe period of treatment. While not being limited by theory, results frompreclinical studies suggest that appropriately timed dailyadministration of bromocriptine in the morning normalizes aberranthypothalamic neurotransmitter activities that induce, potentiate, andmaintain the insulin-resistant, glucose-intolerant state.

Thus, it is believed that a formulation of bromocriptine mesylatemanufactured to improve glycemic control and treat type 2 diabetesshould provide a consistent, rapid and substantially complete release ofthe drug from the formulation to provide the optimum pharmacokineticprofile for treating diabetes. For example, while not being limited bytheory, formulation of bromocriptine mesylate for improving glycemiccontrol should be formulated in a tablet that provides a dose of atleast about 0.8 mg of bromocriptine and which releases at least about80%, or preferably at least about 90%, or at least about 95%, of thedrug within about 30 minutes. Drug release can be measured, for example,using the methods and apparatus described in the U.S. Pharmacopoeia(USP), General Chapter 711, Dissolution, 34^(th) Edition, 2011. Asuitable method for measuring release of bromocriptine mesylate from thetablets described in the present application can use USP Apparatus Type2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid. Thedissolution experiment is typically carried out at about 37° C. Unless aproduct can be manufactured that consistently provides the specifieddose and release profile, the resulting product may be less effectivefor improving glycemic control and treating type 2 diabetes and also mayresult in increased incidence of side-effects.

An accelerated release formulation of bromocriptine mesylate wasdescribed in U.S. Pat. No. 5,679,685, which discusses that acceleratedrelease from bromocriptine mesylate formulations could be achieved byformulating bromocriptine, an antioxidant, a filler, a disintegratingagent, a water scavenging agent and a lubricant. In the preferredformulation, the bromocriptine formulation included bromocriptinemesylate together with citric acid, corn starch, lactose filler andsilicon dioxide and magnesium stearate. Use of anhydrous lactose filleris preferred to minimize moisture content. Citric acid is anantioxidant. Corn starch is a disintegrating agent. Colloidal siliconedioxide acts as a water-scavenger. Magnesium stearate acts as alubricant. While the '685 patent describes the preparation of rapidrelease bromocriptine mesylate on a laboratory scale, difficulties havebeen encountered, however, in manufacturing such a formulation on alarge scale suitable for commercial use because a high degree ofvariation in the dissolution and rate of release of bromocriptinemesylate from the finished drug product, and problems in achievingacceptable product uniformity were found.

One formulation and process for the large scale preparation ofbromocriptine mesylate tablets is described in Example 1. The processfor preparing the tablets on an 80 kg batch scale involved geometricalmixing of the ingredients in several sub-batches followed by finalmixing in a 5 ft³ V-blender followed by discharge into a stainless steelcontainer which was used to feed a 38-station tablet press.

For manufacturing process validation purposes, three 80 kg batches oftablets were prepared using the method described in Example 1. Asdescribed in Example 2, both the dissolution (drug release) propertiesand the tablet content uniformity were measured for samples of tabletsfrom each of the batches. All of the batches showed acceptable drugrelease, where at least about 97% of the drug had been released at about30 minutes as measured using the USP Apparatus Type 2 Paddle Method at50 rpm in 500 mL of 0.1 N hydrochloric acid at 37° C. However, thebatches did not show acceptable content uniformity as two of the threebatches exhibited a relative standard deviation (RSD) bromocriptinecontent greater than the pass criteria. In addition, a trend wasobserved for all three batches in which the highest active ingredientcontent was found in tablets prepared towards the end of the compressionrun, which suggested that the non-uniformity might be accounted for bysettling of the ingredients in the mixture after blending but beforetablet compression was carried out.

A modified process was therefore developed and was carried out asdescribed in Example 3. The tablets contain bromocriptine mesylate(0.945 mg/tablet) together with corn starch (9.00 mg/tablet) as adisintegrant, granular anhydrous citric acid (1.35 mg/tablet), anhydrouslactose (77.58 mg/tablet), colloidal silicon dioxide (0.45 mg/tablet)and magnesium stearate (0.675 mg/tablet). The tablets were prepared asdescribed for the tablets of Example 1, except that the method for thefinal blending and tableting was modified. Based on the reasoning thatthe problem in achieving content uniformity when preparing a formulationas described in Example 1 was likely due to settling of ingredientsafter performing the final blending but before tableting, for example asa result of the transfer of blend from the blender to immediate storagecontainers prior to compression of the blended mixture, the method ofExample 3 was modified to allow transfer of the blended mixture directlyfrom the blending vessel to the tablet press for compression of theblended mixture. This was achieved by modifying the manufacturingprocess so that the final stage of blending was carried out in an in-binhopper where the lubrication and final blending is performed. Followingblending, the lubricated blend is transferred directly from the in-binhopper to the tablet press using a valved transfer chute to avoidsettling of the material prior to tablet compression.

Validation of the manufacturing method described in Example 3 forbromocriptine mesylate tablet manufacture was performed as described inExample 4. Three 80 kg batches of tablets were prepared using thismethod. Both the dissolution (drug release) properties and the tabletcontent uniformity were measured for samples of tablets from each of thebatches. All of the batches showed acceptable drug release, with anaverage of at least about 95% of the drug released at about 30 minutesas measured using the USP Apparatus Type 2 Paddle Method at 50 rpm in500 mL of 0.1 N hydrochloric acid at 37° C. In addition, all of thebatches showed acceptable tablet content uniformity, with RSD valuesthat were significantly lower than the RSD values quoted in Example 2being observed. Therefore, a substantial improvement in tablet contentuniformity was achieved by the modification to the process involvingcarrying out the blending in an in-bin hopper and transferring theblended material directly for tableting via a valved transfer chute.

Based on the results of Example 4, a manufacturing process carried outas described in Example 3 is preferred for manufacturing bromocriptinemesylate tablets suitable for treating type 2 diabetes to providetablets with good content uniformity. Following blending of theformulation ingredients, compression of the mixture is carried outdirectly

Although the method of Example 3 gave bromocriptine mesylate tabletswith good content uniformity, it was unexpectedly found that tabletsmade using the method exhibited poor reproducibility of drug release.

The problem of achieving consistent, rapid drug release from abromocriptine mesylate formulation prepared for improving glycemiccontrol in the treatment of type 2 diabetes is illustrated by the datadescribed in Example 5. Although the validation batches described inExample 4 all had shown an acceptable drug release profile (i.e.,wherein an average of about 95% or greater of the drug release has beenreleased at about 30 minutes), dissolution results obtained with furtherbatches of bromocriptine mesylate tablets manufactured using theformulation and manufacturing process of Example 3 showed substantialvariability in the percentage of drug released at 30 minutes (asdetermined using USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mLof 0.1 N hydrochloric acid at 37° C.). Although certain batches had anacceptable release profile (i.e., about 90% or greater had been releasedat about 30 minutes), several batches had a significantly lower andunacceptable degree of release. See Table 7.

As described in Example 6, an extensive investigation was conducted todetermine the cause of the observed variability. This investigationincluded an evaluation of the analytical method used to determine theamount of bromocriptine dissolved, a review of the raw materials,equipment, operators, batch records, and batch data, and the effect ofvariations in the blend time, tablet hardness, feeder speed, lactoseparticle size, reduced magnesium stearate concentration, removal ofsilicon dioxide, and reduced or increased corn starch concentration. Inaddition, batches of bromocriptine mesylate used in tablet batcheshaving different release profiles were compared using differentialscanning calorimetry to investigate whether a change in form of thebromocriptine might be responsible for the variable drug release. Noneof these investigations succeeded in identifying a reason for thevariable drug release properties that were observed.

Ultimately, the possible role of the particle size of bromocriptinemesylate used in the manufacturing process was investigated. Thebromocriptine mesylate used for the preparation of the tablets wasprepared by a process in which the bromocriptine mesylate crystals weregenerated by addition of methanesulfonic acid at a late stage of theproduction process. Although this process produces high qualitybromocriptine mesylate, it does not control the particle sizedistribution. From measurements of the particle size distributions ofthe bromocriptine mesylate batches used to prepare the various batchesof tablets, it was found that the bromocriptine mesylate batches used toprepare the tablets had a variety of particle size distributions.

It was also found that there was a correlation between the particle sizedistribution and whether or not the tablets manufactured using variousbromocriptine mesylate batches provided release of drug in the mannerrequired for effectively improving glycemic control in the treatment oftype 2 diabetes, as summarized in Table 9. In particular, it was foundthat preparing bromocriptine mesylate tablets from bromocriptinemesylate having a Dv90 of less than about 20 μm consistently provided adrug release profile in which about 90% or more of the bromocriptinemesylate had been released at about 30 minutes. In contrast,bromocriptine mesylate tablets prepared from bromocriptine mesylatehaving a Dv90 of more than about 20 μm failed to consistently provide adrug release profile in which at least 90% of the bromocriptine mesylatehad been released at about 30 minutes. The correlation betweenbromocriptine mesylate particle size and dissolution is shown ingraphical form in FIG. 1.

It was also found that there was a correlation between the span of thevolume-based particle size distribution and drug release. Preparingbromocriptine mesylate tablets from bromocriptine mesylate with aparticle-size distribution having a span of less than about 2.0consistently provided a drug release profile in which 90% or more of thedrug had been released at about 30 minutes, whereas bromocriptinemesylate tablets prepared from bromocriptine mesylate having avolume-based particle distribution having a span of greater than about 2did not consistently provide a drug release profile wherein at leastabout 90% of the drug had been release at about 30 minutes. Thecorrelation between bromocriptine mesylate particle-size distributionspan and dissolution is shown in graphical form in FIG. 2.

Based on the foregoing results, it has therefore been discovered thatthe manufacture of bromocriptine mesylate tables for improving glycemiccontrol in patients with type 2 diabetes can be improved significantlyby carefully controlling the size of the bromocriptine mesylateparticles used in manufacturing the tablets. By controlling the particlesize, tablets can be manufactured which consistently provide a releaseprofile wherein about 90% or greater of the drug has been released atabout 30 minutes thereby ensuring that the product is produced with aconsistently acceptable potency and safety profile for improvingglycemic control and treating type 2 diabetes. This is particularlyuseful when a manufacturing method is employed that achieves improvedcontent uniformity by employing direct transfer of the bromocriptineformulation mixture for tableting after blending without allowing timefor the ingredients to settle in the blended mixture Advantages includethe ability to reproducibly produce drug product with a defined drugcontent and drug release profile to meet quality standards mandated bydrug regulatory authorities such as the Food and Drug Administration.

Based on the foregoing studies, the inventors have found methods that,by using bromocriptine mesylate with controlled particle size as well asother methods described herein, bromocriptine mesylate tablets that aresuitable for improving type 2 diabetes can be prepared with consistentlygood drug release properties as well as with good content uniformity.

One method that has been found useful is to control the particle size byuse of micronized bromocriptine mesylate. In one aspect, it has beendiscovered that a superior bromocriptine mesylate formulation forimproving glycemic control and treating type 2 diabetes can be preparedby using micronized bromocriptine mesylate for manufacturingbromocriptine mesylate tablets. The micronized bromocriptine mesylatemay have a Dv90 of less than about 10 μm. In some embodiments, themicronized bromocriptine has a Dv90 of less than about 5 μm.

In some embodiments, the micronized bromocriptine mesylate has a Dv99 ofless than about 15 μm. In some embodiments, the micronized bromocriptinemesylate has a Dv99 of less than about 10 μm.

In some embodiments, the micronized bromocriptine mesylate has avolume-based particle size distribution wherein not more than about 20%of the bromocriptine mesylate has a particle size of less than about 1μm.

In some embodiments, the micronized bromocriptine mesylate has avolume-based particle size with a Dv99 of less than about 15 μm; a Dv90of less than about 10 μm; and wherein not more than about 20% of thebromocriptine mesylate has a particle size of less than about 1 μm.

The bromocriptine mesylate tablet prepared using micronizedbromocriptine is formulated to provide a dissolution profile such that,when tested in USP Apparatus Type 2 paddle method at 50 rpm in 500 mL of0.1 N hydrochloric acid at about 37° C., the tablet has released atleast about 80%, preferably at least about 90% of the bromocriptinemesylate at about 30 minutes. Preferably, the bromocriptine mesylatetablet provides a dissolution profile such that the tablet has releasedat least about 95% of the bromocriptine mesylate at about 30 minutes. Insome embodiments, the bromocriptine mesylate tablet provides adissolution profile such that the tablet has released at least about80%, and preferably at least about 90%, of the bromocriptine mesylate atabout 20 minutes.

Although the bromocriptine mesylate tablet is formulated to provide adissolution profile such that, when tested in USP Apparatus Type 2paddle method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about37° C., the tablet has released at least about 80%, preferably about90%, or most preferably about 95%, of the bromocriptine mesylate atabout 30 minutes, extremely rapid release of bromocriptine mesylate fromthe formulation may not be desired, since a formulation that releasesbromocriptine extremely rapidly may result in an undesired spike in invivo drug levels and may not be suitable for treating type 2 diabetes,or give rise to side-effects. Therefore, in some embodiments, thebromocriptine mesylate tablet prepared using micronized bromocriptinemesylate is formulated to provide a dissolution profile such that, whentested in USP Apparatus Type 2 paddle method at 50 rpm in 500 mL of 0.1N hydrochloric acid at about 37° C., not more than about 75%, not morethan about 60%, or not more than about 50% of the bromocriptine mesylatehas been released at about 7 minutes, and/or not more than about 90%,not more than about 85%, not more than about 80%, or, not more thanabout 75% of the bromocriptine mesylate has been released at about 10minutes. The release profiles may be achieved by producing bromocriptinemesylate tablets using bromocriptine mesylate having a particularparticle size distribution so that the finished drug productconsistently provides a dissolution profile that is suitable fortreatment of type 2 diabetes.

The bromocriptine mesylate tablet prepared using micronizedbromocriptine mesylate is formulated to provide a pharmacokineticprofile wherein the time to maximum plasma concentration (T_(max))following administration of six bromocriptine mesylate tablets, eachproviding a dose of about 0.8 mg of bromocriptine, is between about 30and about 60 minutes, such as about 50 minutes, e.g. about 53 minutes,when the tablets are administered under fasting conditions, or betweenabout 90 and about 120 minutes, when the tablets are administered underhigh fat fed conditions, to adult subjects.

The bromocriptine mesylate tablet may contain an amount of bromocriptinemesylate that provides a dose of at least about 0.8 mg of bromocriptinemesylate per tablet.

The formulations disclosed herein may further include citric acid.Citric acid may act as an antioxidant to improve the stability of thebromocriptine, but also may enhance bromocriptine absorption. Otherantioxidants which may be used include. but are not limited to, vitaminsA, C, E, beta-carotene, zinc, selenium, glutathione, coenzyme Q-10 andechinacea. The formulations disclosed herein may also include one ormore disintegrating agent. Examples of suitable disintegrating agentsinclude, but are not limited to, corn starch, sodium starch glycolate,sodium carboxymethyl cellulose, calcium carboxymethyl cellulose,croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substitutedhydroxypropyl cellulose, starch, pregelatinised starch and sodiumalginate. The formulations disclosed herein may also include one or morediluents. Examples of suitable diluents include, but are not limited to,lactose (e.g., monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate. Theformulations disclosed herein may also include one or more lubricants.Examples of suitable lubricants include, but are not limited to,magnesium stearate, colloidal silicon dioxide, calcium stearate, zincstearate, stearic acid, talc, glyceryl behenate, polyethylene glycol,polyethylene oxide polymers, sodium lauryl sulfate, magnesium laurylsulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidalsilica, and others as known in the art. In some embodiments, theformulation used is prepared substantially as described in Example 9using micronized bromocriptine mesylate.

Micronization provides for reduction of particle size to provideparticles that are on the order of microns in diameter as measured bymethods known to those of ordinary skill in the art, such as the volumedistribution method. Methods of micronizing bromocriptine mesylate toafford formulations disclosed herein include those that are known tothose of ordinary skill in the art and include, but are not limited to,milling, grinding, and the use of supercritical fluids. For example, onemethod of micronization (the “rapid expansion of supercriticalsolutions” or RESS method), material is dissolved in supercritical fluidunder high temperature and pressure and the resulting solution isexpanded through a nozzle to form small particles.

Micronization by jet milling is a method that can be used to produceparticles in the lower micrometer range, and is the preferred method formicronizing bromocriptine mesylate. In brief, the raw material with amaximum size of about 1 to 2 mm is introduced into the milling chambervia a gas stream. Within the milling chamber a circular gas streamaccelerates the particles which are micronized by collision with eachother or with the wall of the chamber. The ground particles are removedfrom the milling chamber by the gas stream, while the larger ones stayinside due to centrifugal forces. In the preferred process formicronizing bromocriptine, micronization is performed using a jet millunder a nitrogen atmosphere at a controlled temperature of about 0° C.

Example 7 describes the preparation of batches of micronizedbromocriptine mesylate and characterization of their properties. Asshown in Table 10, micronization produced bromocriptine material withsimilar particle size distributions after micronization even whenbromocriptine mesylate batches with rather different materials were usedas the starting material. Exemplary particle size distributions for abatch of bromocriptine mesylate before and after micronization are shownin FIGS. 3A and 3B.

Example 8 illustrates the improved and consistent drug release profilesthat can be achieved by employing micronized bromocriptine mesylate toprepare bromocriptine mesylate tablets. Tablets prepared with micronizedbromocriptine mesylate had significantly improved drug release (98% ofthe bromocriptine released by 30 minutes) compared to tablets preparedfrom the same batch of bromocriptine mesylate without micronization(which released only 69% of the bromocriptine mesylate at 30 minutes).

The relationship between particle size distribution and drugrelease/dissolution for bromocriptine mesylate is further illustrated inFIG. 4. FIG. 4 shows plots of the cumulative volume-based particle sizedistribution for three batches of bromocriptine mesylate: a batch ofbromocriptine mesylate which was used in a bromocriptine mesylate tabletformulation (prepared as described in Example 3) which had released 96%of the bromocriptine mesylate at 30 minutes when tested in USP ApparatusType 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid atabout 37° C.; a batch of bromocriptine mesylate which was used in abromocriptine mesylate tablet formulation (prepared as described inExample 3) which had released about 78% of the bromocriptine mesylate at30 minutes when tested in USP Apparatus Type 2 Paddle Method at 50 rpmin 500 mL of 0.1 N hydrochloric acid at about 37° C.; and a batch ofmicronized of bromocriptine mesylate.

In another aspect, it has been discovered that a method of manufacturinga bromocriptine mesylate formulation for improving glycemic control intreating type 2 diabetes using a manufacturing process that selectivelycontrols bromocriptine mesylate particle size, for example by employingparticle size measurement and/or processing bromocriptine mesylate toreduce the particle size, to prepare bromocriptine mesylate tabletsthat, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500mL of 0.1 N hydrochloric acid at about 37° C. consistently provide adrug release profile wherein at least 90%, and preferably at least 95%,of the drug is released within about 30 minutes. The result is achievedby controlling the particle size distribution of the bromocriptinemesylate to be within the particle size range that has been found toresult in bromocriptine tablets having the desired drug release profile.

In some embodiments, particle size measurement is employed to selectbromocriptine mesylate having a particle size distribution thatconsistently provides a drug release profile wherein at least about 80%,or preferably least about 90%, or at least about 95%, of the drug isreleased within about 30 minutes. The method comprises determining thatthe bromocriptine mesylate has a particle size distribution whichprovides the requisite drug release profile and subsequently blendingthe bromocriptine mesylate of determined particle size distribution withexcipients to form a mixture wherein the bromocriptine mesylate issubstantially evenly distributed in the mixture, and then compressingthe mixture to form one or more tablets. The tablet may comprise anamount of bromocriptine mesylate that provides a dose of at least about0.8 mg of bromocriptine. The tablet may provide a dissolution profile,when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of0.1 N hydrochloric acid at about 37° C., wherein at least about 80%, orpreferably at least about 90% or about 95%, of the bromocriptinemesylate has been released at about 30 minutes. The method preferablycomprises determining that the bromocriptine mesylate has a Dv90 of lessthan about 20 μm. It is not essential to determine the volume-basedparticle size distribution per se since other methods of measuring theparticle size distribution (such as number-based or mass-based methods)could be used. The method should, however, comprise determining that thebromocriptine mesylate particle size distribution is equivalent to aDv90 of less than about 20 μm.

In some embodiments, particle size measurement is employed to selectbromocriptine mesylate having a particle size distribution thatconsistently provides a drug release profile wherein at least about 80%,and preferably at least about 90%, of the bromocriptine mesylate hasbeen released at about 20 minutes when tested in USP Apparatus Type 2Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about37° C.

In some embodiments, particle size measurement is employed to selectbromocriptine mesylate having a particle size distribution thatconsistently provides a drug release profile wherein not more than about75%, not more than about 60%, or not more than about 50% of thebromocriptine mesylate has been released at about 7 minutes when testedin USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 Nhydrochloric acid at about 37° C., and/or not more than about 90%, notmore than about 85%, not more than about 80%, or not more than about75%, of the bromocriptine mesylate has been released at about 10 minuteswhen tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of0.1 N hydrochloric acid at about 37° C.

In some embodiments, particle size measurement is employed to selectbromocriptine mesylate having a particle size distribution thatconsistently provides a tablet with a pharmacokinetic profile whereinthe time to maximum plasma concentration (T_(max)) followingadministration of six bromocriptine mesylate tablets, each providing adose of about 0.8 mg of bromocriptine, is between about 30 and about 60minutes, such as about 50 minutes, e.g. about 53 minutes, when thetablets are administered under fasting conditions, or between about 90and about 120 minutes, when the tablets are administered under high fatfed conditions, to adult subjects.

The size of the bromocriptine mesylate particles and the particle sizedistribution may be determined by any of several methods. Methods usefulfor analyzing particle size within the range of about 10 nm to 100 μm,include, but are not limited to: laser diffraction particle sizeanalysis, mechanical sieving, optical microscopy, ultracentrifugation,sedimentation, air permeability, electron microscopy, scanning electronmicroscopy and Coulter Counter techniques. Methods for determiningparticle size are described, for example, in Martin et al., PhysicalPharmacy, 3rd Ed., Lea & Febiger, Philadelphia (1983); and Merkus etal., Particle Size Measurements, Fundamentals, Practice, Quality,Springer (2009).

Optical microscopy is useful for particle size measurement in the rangeof about 0.2 μm to about 100 μm. For optical microscopy, an emulsion orsuspension, diluted or undiluted, is mounted on a slide or ruled cell.The microscope eyepiece is fitted with a micrometer by which the size ofthe particles may be estimated.

Mechanical sieving uses a series of standard sieves calibrated by theNational Bureau of Standards. Mechanical sieves may be used forscreening material as fine as 44 μm (No. 325 sieve). Sieves manufacturedby photo-etching and electroforming are available with apertures from 90μm to 5 μm.

Measurements obtained using laser diffraction are preferred. Thesetechniques operate on the principle that different sizes of particlesproduce a different diffraction pattern, which depends on the size ofthe particle. In laser particle size analysis, laser light which hasbeen passed through a sample of particles is scattered onto a Fourierlens that focuses the scattered light onto a detector array. Aninversion algorithm is used to infer the particle size distribution fromthe collected diffracted light data.

Laser diffraction measurement of particle size can use a dry method(wherein a suspension of the compound/salt in an airflow crosses thelaser beam) or a wet method (wherein a suspension of the compound/saltin a liquid dispersing medium, such as isooctane or about 0.05% lecithinin isooctane or (e.g., if compound is soluble in isooctane) 0.1% Tween80 in water, crosses the laser beam. With laser diffraction, particlesize is preferably calculated using the Fraunhofer calculation; and/orpreferably a Sympatec or Malvern Mastersizer apparatus is used formeasurement.

The particle size distribution ranges defined herein are based uponmeasurements made using technology and instruments using laser particlesize analysis using the instruments and methods developed by SYMPATECGmbH, in particular Sympatec HELOS which can provide particle sizeanalysis of dry and wet samples, i.e., of powders, suspensions,emulsions or sprays and is built to the specifications of ISO 13320“Particle size analysis—laser diffraction methods.”

Notwithstanding expected variability in the precise values for particlesize and particle size distribution measurements obtained usingdifferent instruments and analytical methods, the claims are notintended to be limited by or to a particular method of particle-sizemeasurement or analysis.

In some embodiments, the particle size of the bromocriptine mesylateused to make bromocriptine mesylate tablet is controlled by including inthe manufacturing process a step of processing bromocriptine mesylate toreduce its average particle size so as to provide bromocriptine mesylatethat has a Dv90 of less than about 20 μm. The bromocriptine mesylateused as a starting material may have a Dv90 of more than about 20 μm andthe processing may include reducing the size of bromocriptine mesylateparticles (e.g., by grinding, milling, or micronization) or sieving toremove larger particles. After the bromocriptine mesylate particle sizehas been reduced, the bromocriptine mesylate is blended with excipientsto form a mixture wherein the bromocriptine mesylate is evenlydistributed in the mixture, and then the mixture is compressed to formone or more tablets. The tablet may comprise an amount of bromocriptinemesylate that provides a dose of at least about 0.8 mg of bromocriptine.The tablet may provide a dissolution profile, when tested in USPApparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloricacid at about 37° C., wherein at least about 80%, preferably at leastabout 90%, or at least about 95%, of the bromocriptine mesylate has beenreleased at about 30 minutes. In some embodiments, the tablet mayprovide a dissolution profile, when tested in USP Apparatus Type 2Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about37° C., wherein at least about 80%, or at least about 90%, of thebromocriptine mesylate has been released at about 30 minutes. In someembodiments, the tablet may provide a dissolution profile, when testedin USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 Nhydrochloric acid at about 37° C., wherein not more than about 75%, notmore than about 60%, or not more than about 50% of the bromocriptinemesylate has been released at about 7 minutes, and/or not more thanabout 90%, not more than about 85%, not more than about 80% or, not morethan about 75% of the bromocriptine mesylate has been released at about10 minutes.

In some embodiments, the tablet may have a pharmacokinetic profilewherein the time to maximum plasma concentration (T_(max)) followingadministration of six bromocriptine mesylate tablets, each providing adose of about 0.8 mg of bromocriptine, is between about 30 and about 60minutes, such as about 50 minutes, e.g. about 53 minutes, when thetablets are administered under fasting conditions, or between about 90and about 120 minutes, when the tablets are administered under high fatfed conditions, to adult subjects.

In some embodiments of the methods described above, the bromocriptinemesylate used for manufacturing the tablets is selected or processed tohave a Dv90 of less than about 20 μm, less than about 18 μm, less thanabout 16 μm, less than about 15 μm, less than about 10 μm, or less thanabout 5 μm. In some embodiments, the bromocriptine mesylate used formanufacturing the tablets is selected or processed to have a Dv50 ofless than about 10 μm, less than about 8 μm, less than about 7 μm, orless than about 5 μm. In some embodiments, the bromocriptine mesylateused for manufacturing the tablets is selected or processed to have aDv10 of less than about 5 μm, less than about 3 μm, or less than about 2μm. In some embodiments of the methods described above, thebromocriptine mesylate used for manufacturing the tablets is selected orprocessed to have a volume-based particle size distribution such thatnot more than about 40%, not more than about 20%, not more than 10% ornot more than about 5% of the bromocriptine mesylate has a particle sizeof less than about 1 μm.

In some embodiments, the bromocriptine mesylate used for manufacturingthe tablets is selected or processed to have a particle size such thatthe particle size distribution has a Dv90 of about 20 μm or lower, aDv50 of about 10 μm or lower and a Dv10 of about 5 μm or lower. In someembodiments, the bromocriptine mesylate used for manufacturing thetablets is selected or processed to have a particle size such that theparticle size distribution has a Dv90 of about 15 μm or lower, a Dv50 ofabout 8 μm or lower and a Dv10 of about 3 μm or lower. In someembodiments, the bromocriptine mesylate used for manufacturing thetablets is selected or processed to have a particle size such that theparticle size distribution has a Dv90 of about 10 μm or lower, a Dv50 ofabout 5 μm or lower and a Dv10 of about 3 μm or lower. In someembodiments, the bromocriptine mesylate used for manufacturing thetablets is selected or processed to have a particle size such that theparticle size distribution has a Dv90 of about 8 μm or lower, a Dv50 ofabout 5 μm or lower and a Dv10 of about 3 μm or lower. In someembodiments, the bromocriptine mesylate used for manufacturing thetablets is selected or processed to have a particle size such that theparticle size distribution has a Dv90 of about 5 μm or lower, a Dv50 ofabout 3 μm or lower and a Dv10 of about 1 μm or lower.

In some embodiments bromocriptine mesylate used for manufacturing thetablets is selected or processed to have a volume-based particle sizesuch that the particle size span is about 3 or lower, about 2.5 orlower, or about 2 or lower.

In addition, in some embodiments, particle size measurement as describedabove and processing to reduce the average particle size may be combinedto provide additional control in preparing bromocriptine mesylatetablets. For example, following processing to reduce the averageparticle size, particle size measurement may be performed to ensure thatthe particle size distribution is within a range that providesconsistent drug release. In addition, micronization may be employed as atechnique to reduce the particle size to prepare a bromocriptinemesylate tablet that comprises micronized bromocriptine as described ingreater detail above.

The bromocriptine mesylate tablet prepared by the methods describedherein may be formulated with citric acid. The formulation may alsoinclude a disintegrating agent. In some embodiments, the disintegratingagent is corn starch. In some embodiments, the formulation furthercomprises lactose, colloidal silicon dioxide and magnesium stearate. Insome embodiments, the bromocriptine mesylate tablets are preparedsubstantially as described in Example 1.

As discussed above, the data provided in Example 8 (Table 11) illustratethe effect of processing bromocriptine mesylate to improve and provideconsistent dissolution properties and show that a significantly greaterdegree of drug release (at 30 minutes) was obtained from tabletsmanufactured using micronized bromocriptine mesylate as compared to thesame batch of bromocriptine mesylate without micronization. The dataalso demonstrate the effectiveness of controlling particle size andemploying processing to reduce the bromocriptine mesylate particle sizefor consistently producing a drug product with superior releaseproperties.

The bromocriptine mesylate tablets described herein, and bromocriptinemesylate tablets prepared by the methods herein, may be used to treattype 2 diabetes by improving glycemic control in an individual with type2 diabetes. The tablet is administered within about two hours afterwaking in the morning with food. The initial dose is about 0.8 mg ofbromocriptine daily, which is increased weekly by one tablet until amaximal tolerated daily dose of about 1.6 to about 4.8 mg (2 to 6tablets) is achieved.

EXAMPLES

The inventors' discoveries are illustrated by the following examples,which are not intended to limit the scope of the claims. Othervariations or embodiments of the invention will also be apparent to oneof ordinary skill in the art from the above descriptions and thefollowing Examples.

Example 1 Preparation of a Bromocriptine Mesylate Tablet Formulation

Bromocriptine mesylate tablets are prepared having the ingredientslisted in Table 1 below.

TABLE 1 Bromocriptine Mesylate Tablet Formulation. Quantity QuantityIngredient (mg/tablet) (kg/batch) Bromocriptine mesylate USP 0.945 0.84Corn starch NF 9.00 8.00 Granular anhydrous citric acid USP 1.35 1.20Anhydrous lactose NF 77.58 69.00 Colloidal silicon dioxide NF 0.45 0.40Magnesium Stearate NF 0.675 0.60 Total Weight 90.0 80.0

The tablets were prepared by geometrical mixing via trituration ofbromocriptine mesylate (Euticals S.p.a., Milan) with corn starch as fourtriturations in a PK BlendMaster™ V-Blender. Sequentially, two sub-loadsof granular anhydrous citric acid and corn starch were mixed in a PKBlendMaster™. These two sub-loads were each divided into two equalsub-loads, yielding a total of four sub-loads. Each of the fourbromocriptine mesylate triturations was then mixed with adjusted amountsof anhydrous lactose, corn starch and one citric acid/starch cornsub-load in a Fielder PMA 65 mixer to form four premixes [A-D]. A 2.0 kgquantity was removed after Premix A for mixing in a PK BlendMaster™ withcolloidal silicon dioxide and magnesium stearate to form a lubricantpremix. The four premixes were then loaded in sequential order, with thelubricant premix loaded in between premixes B and C, into a 5 ft³V-blender where lubrication/final blending was performed. The lubricatedblend was then discharged into a stainless steel container which wasused to feed a 38-station HATA tablet press. The tablets were compressedusing the tablet press.

Example 2 Validation Studies for Tablets Prepared According to Example 1

Three batches were prepared using the method described in Example 1 tovalidate the manufacturing method.

Drug release profiles for samples of the tablets were measured using theUSP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 Nhydrochloric acid at 37° C. Table 2 below shows the drug releaseprofiles obtained for tablets from each batch.

TABLE 2 Drug Release from Three Batches of Bromocriptine MesylateTablets Prepared as Described in Example 1. Time Average % Release BatchNo. (minutes) (n = 12) 1 10 78 20 96 30 99 40 100 2 10 72 20 91 30 97 4098 3 10 81 20 95 30 100 40 101

In addition, blend uniformity and tablet content uniformity wereassessed.

Blend uniformity was assessed by assaying the content of the powderedformulation at ten locations in the blender following final blending butbefore tableting. All of the batches met the criteria for blenduniformity.

Tablet content uniformity was evaluated on a sample of 60 tablets fromeach batch. The tablets were assayed to assess, inter alia, the amountof bromocriptine present in the tablet relative to the label amount of0.8 mg of bromocriptine. In addition, the mean and relative standarddeviation (RSD) bromocriptine mesylate content was calculated for eachbatch. The content uniformity results obtained are summarized in Table3. The tablet content uniformity requirements were not met for batches 2and 3. In addition, a trend was observed for all three batches in whichthe highest active ingredient content was found in tablets preparedtowards the end of the compression run.

TABLE 3 Content Uniformity Evaluation for Three Batches of BromocriptineMesylate Tablets Prepared as Described in Example 1 (n = 60 tablets foreach batch). Bromocriptine Content (% of label) RSD Pass Batch No. MeanRange RSD Criterion^(†) Pass/Fail 1 101.5 95.4-108.9 3.13 4.52 Pass 2103.0 96.7-113.2 4.03 4.01 Fail 3 100.5 92.2-113.1 5.05 4.85 Fail^(†)The RSD pass criteria vary according to the bromocriptine contentand are calculated using Bergum's method. Meeting the criterion provides90% assurance that at least 95% of future samples from the samepopulation would pass the USP content uniformity test

Example 3 Modified Procedure for the Preparation of a BromocriptineMesylate Tablet Formulation

Bromocriptine mesylate tablets were prepared having the ingredientslisted in Table 4 below.

TABLE 4 Bromocriptine Mesylate Tablet Formulation. Quantity QuantityIngredient (mg/tablet) (kg/batch) Bromocriptine mesylate USP 0.945 0.84Corn starch NF 9.00 8.00 Granular anhydrous citric acid USP 1.35 1.20Anhydrous lactose NF 77.58 69.00 Colloidal silicon dioxide NF 0.45 0.40Magnesium Stearate NF 0.675 0.60 Total Weight 90.0 80.0

The tablets were prepared by geometrical mixing via trituration ofbromocriptine mesylate (Euticals S.p.a., Milan) with corn starch as fourtriturations in a PK BlendMaster™ V-Blender. Sequentially, two sub-loadsof granular anhydrous citric acid and corn starch were mixed in a PKBlendMaster™. These two sub-loads were each divided into two equalsub-loads, yielding a total of four sub-loads. Each of the fourbromocriptine mesylate triturations was then mixed with adjusted amountsof anhydrous lactose, corn starch and one citric acid/starch cornsub-load in a Fielder PMA 65 mixer to form four premixes [A-D]. A 2.0 kgquantity is removed after Premix A for mixing in a PK BlendMaster™ withcolloidal silicon dioxide and magnesium stearate to form a lubricantpremix. The four premixes were then loaded in sequential order, with thelubricant premix loaded in between premixes B and C, into an 8 ft³in-bin hopper; where lubrication/final blending was performed. Thelubricated blend was then transferred from the in-bin hopper to a tabletpress using a valved transfer chute, and then compressed using a38-station Hata tablet press.

Example 4 Validation Studies for Tablets Prepared According to Example 3

To validate the manufacturing method, three batches were prepared usingthe method described in Example 3.

Drug release profiles for samples of the tablets were measured using theUSP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 Nhydrochloric acid at 37° C. Table 5 below shows the drug releaseprofiles obtained for tablets from each batch.

TABLE 5 Drug Release from Three Batches of Bromocriptine MesylateTablets Prepared as Described in Example 3. Time Average % Release BatchNo. (minutes) (n = 12) 1 10 91 20 101 30 104 40 103 2 10 84 20 100 30103 40 104 3 10 83 20 95 30 97 40 98

In addition, blend uniformity and tablet content uniformity wereassessed.

Blend uniformity was assessed by assaying the content of the powderedformulation at ten locations in the blender following final blending butbefore tableting. All of the batches met the criteria for blenduniformity.

Tablet content uniformity was evaluated on a sample of 60 tablets fromeach batch. The tablets were assayed to assess, inter alia, the amountof bromocriptine present in the tablet relative to the label amount of0.8 mg of bromocriptine. In addition, the mean and relative standarddeviation (RSD) bromocriptine mesylate content was calculated for eachbatch. The content uniformity results obtained are summarized in Table6. In this case all three batches met the tablet content uniformityrequirements, with RSD values that were significantly lower than the RSDvalues quoted in Example 2 being observed.

TABLE 6 Content Uniformity Evaluation for Three Batches of BromocriptineMesylate Tablets Prepared as Described in Example 4 (n = 60 tablets foreach batch). Bromocriptine Content (% of label) RSD Pass Batch No. MeanRange RSD Criterion^(†) Pass/Fail 1 102.5 98.6-110.4 1.83 4.18 Pass 2101.5 96.9-107.0 2.24 4.52 Pass 3 100.8 95.7-105.9 1.83 4.75 Pass^(†)The RSD pass criteria vary according to the bromocriptine contentand are calculated using Bergum's method. Meeting the criterion provides90% assurance that at least 95% of future samples from the samepopulation would pass the USP content uniformity test

Example 5 Evaluation of Drug Release from Bromocriptine Mesylate TabletPreparations

Over a period of time, a number of batches of bromocriptine mesylatetablets were prepared by methods substantially similar to the methoddescribed in Example 1 using micronized bromocriptine mesylate purchasedfrom Euticals, S.p.a. Drug release from each batch of tablets wasmeasured using USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of0.1 N hydrochloric acid at 37° C. at 30 minutes. The result of the drugrelease measurements, showing the percentage of drug released at about30 minutes for each batch (entries 2, 3, 4, 5, 6, 16, 17, 20 and 22 arefor single tablet batches, other entries represent data from multipletablet batches) is summarized in Table 7 below.

TABLE 7 Dissolution Results Showing Percentage of Bromocriptine MesylateReleased at 30 Minutes From Different Batches of Bromocriptine MesylateTablets Prepared by Methods Substantially Similar to Example 1. AveragePercentage Released at Table Entry about 30 minutes (n = 6 to 24) 1 96 293 3 93 4 93 5 91 6 91 7 94 8 95 9 96 10 97 11 98 12 98 13 99 14 104 1589 16 91 17 91 18 92 19 92 20 87 21 87 22 87 23 89 24 78 25 89 26 82 2784 28 68 29 72 30 76

Example 6 Investigation of the Cause of Variable Drug Release fromBromocriptine Mesylate Tablet Preparations

An investigation was conducted into potential reasons for the variabledrug release from different bromocriptine mesylate tablet preparations.The investigation covered analytical as well as manufacturing sourcesfor the unexpected drug release results.

A number of variables in the HPLC analytical method used to measure theextent of drug release were investigated. Although it was found thatminor improvements to reduce variability could be achieved, for exampleby using low actinic glassware, a chilled HPLC autosampler, anddisposable plastic syringes, the variability could not be attributed tolaboratory causes alone.

Investigation of the manufacturing process included numerous aspects ofthe production process, including the raw materials, equipment,operators, batch records, and batch data without identifying a rootcause. As a result, smaller scale studies were designed to evaluateformulation variables and key operational variables of the productionprocess. A summary of these studies and results obtained are provided inTable 8.

TABLE 8 Summary of Process Investigations Conducted to Investigate theCause of Variable Drug Release from Bromocriptine Mesylate TabletPreparations. Study Description Dissolution Results Low lubricationblend time Comparable to Control High lubrication blend time Comparableto Control Low tablet hardness Comparable to Control High tablethardness Comparable to Control Low feeder speed Comparable to ControlHigh feeder speed Comparable to Control Small particle size lactoseComparable to Control Reduced magnesium stearate concentrationComparable to Control Removal of silicon dioxide Comparable to ControlReduced corn starch concentration Comparable to Control Increased cornstarch concentration Comparable to Control

Finally, the possible role of the particle size of bromocriptinemesylate used in the manufacturing process was investigated. Thevolume-based particle size distribution for the bromocriptine mesylateused in preparing the tablet batches was measured by laserdiffractometry using a Sympatec HELOS Laser Diffractometer. The resultsare shown in Table 9, which lists the bromocriptine particle sizedistribution that was determined for the various batches ofbromocriptine mesylate and the percentage drug that was released by 30minutes determined for each of the batches.

TABLE 9 Dissolution Results Showing the Relationship Between thePercentage of Bromocriptine Mesylate Released at 30 Minutes Batches ofBromocriptine Mesylate Tablets and the Particle Size Distributions ofthe Bromocriptine Mesylate Used for Tablet Preparation. Average Percent-age Released at Table about 30 minutes Entry Dv10 Dv50 Dv90 Span (n = 6to 24) 1 1.5 4.2 12.6 2.7 96 2 1.5 4.2 12.6 2.7 93 3 1.8 5.3 14.4 2.4 934 1.6 4.6 12.3 2.3 93 5 1.8 5.3 14.4 2.4 91 6 2.4 7.2 15.3 1.8 91 7 2.47.2 15.3 1.8 94 8 2.4 7.2 15.3 1.8 95 9 2.4 7.2 15.3 1.8 96 10 2.4 7.215.3 1.8 97 11 2.4 7.2 15.3 1.8 98 12 2.4 7.2 15.3 1.8 98 13 2.4 7.215.3 1.8 99 14 2.4 7.2 15.3 1.8 104 15 3.1 10.4 28.1 2.4 89 16 3.1 10.428.1 2.4 91 17 2.4 7.2 15.3 1.8 91 18 3.1 10.4 28.1 2.4 92 19 3.1 10.428.1 2.4 92 20 3.1 10.4 28.1 2.4 87 21 3.1 10.4 28.1 2.4 87 22 3.1 10.428.1 2.4 87 23 3.1 10.4 28.1 2.4 89 24 3.9 13.7 57.4 3.9 78 25 3.1 10.428.1 2.4 89 26 3.1 10.4 28.1 2.4 82 27 3.1 10.4 28.1 2.4 84 28 2.3 7.925.8 3.0 68 29 2.3 7.9 25.8 3.0 72 30 2.3 7.9 25.8 3.0 76

The results show a correlation between the drug release and the particlesize distribution of the bromocriptine mesylate that was used to preparethe tablet batch. Tablets prepared using bromocriptine mesylateparticles where the Dv90 was less than about 20 μm consistently provideda release profile wherein 90% or greater of the drug had been releasedat about 30 minutes. In contrast, material with a particle sizedistribution greater than about 20 μm provided variable or low drugrelease. The correlation between percent drug release and Dv90 isplotted in FIG. 1.

In addition, the particle-size distribution span was also correlatedwith drug release. The correlation between percent drug release and theparticle-size distribution span is plotted in FIG. 2.

Example 7 Micronization of Bromocriptine Mesylate

Bulk batches of bromocriptine mesylate were micronized using a jet millunder a nitrogen atmosphere at a controlled temperature of 0° C. Thevolume particle size distribution was measured using a Sympatec HELOSH1013 Laser Diffractometer. Table 10 shows the bromocriptine mesylateparticle size distribution measured for each batch of bromocriptinemesylate before and after micronization demonstrating that micronizationof bulk materials having quite different particle size distributionsbefore micronization resulted in micronized materials with similarparticle size distributions. FIG. 3A shows the volume-based particlesize distribution measured for the material of Table 6 Entry 1 beforemicronization and FIG. 3B shows the volume-based particle sizedistribution measured for the same material after micronization.

The impurity profile (percentage of major impurities), X-ray powderdiffraction pattern, I.R. spectra, and differential scanning calorimetrythermograms of the bromocriptine mesylate batches before and aftermicronization were also investigated. No significant differences wereobserved, suggesting that the micronization process does not modify thepurity or solid state form of the bromocriptine mesylate.

TABLE 10 Bromocriptine Mesylate Particle Size Distributions Before andAfter Micronization. Before Micronization After Micronization Table % %Entry <1 μm % <10 μm % <15 μm <1 μm % <10 μm % <15 μm 1 1 19 29 8 97 1002 1 55 77 6 98 100 3 1 31 45 9 98 100

Example 8 Effect of Micronizing Bromocriptine Mesylate to Improve DrugRelease Properties

The data provided in Table 11 illustrate the effect of processingbromocriptine mesylate to improve and provide consistent dissolutionproperties. Bromocriptine mesylate tablets were prepared substantiallyaccording to the method described in Example 3 above, wherein saidmethods include geometric dilution and diffusional blending, and thedissolution of the tablets (n=12) was measured tested in USP ApparatusType 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at37° C. The tablets prepared were identical except that one batch oftablets (Table Entry 1) was prepared using (non-micronized)bromocriptine mesylate as obtained from the active pharmaceuticalingredient manufacturer (Euticals S.p.a., Milan), whereas another batchof tablets was prepared using the same batch of bromocriptine mesylatebut which was further processed by micronization prior to being used fortablet manufacture (Table Entry 2). The data that tablets prepared withmicronized bromocriptine mesylate had significantly improved drugrelease (at 30 minutes) compared to tablets prepared from the same batchof bromocriptine mesylate without micronization.

TABLE 11 Dissolution Results Showing Percentage of BromocriptineMesylate Released at 30 Minutes from Different Batches of BromocriptineMesylate Tablets. Percent bromo- Particle Size Distribution criptinereleased Table Bromocriptine Dv10 Dv50 Dv90 at 30 minutes Entry Used(μm) (μm) (μm) (n = 12 Tablets) 1 Bromocriptine 1.4 5.8 26.7 69 mesylatewithout micronization 2 Micronized 0.7 1.5 3.1 98 bromocriptine mesylate

Example 9 Procedure for the Preparation of a Bromocriptine MesylateTablet Formulation Using Micronized Bromocriptine Mesylate

Bromocriptine mesylate tablets were prepared having the ingredientslisted in Table 12 below.

TABLE 12 Bromocriptine Mesylate Tablet Formulation. Quantity QuantityIngredient (mg/tablet) (kg/batch) Micronized bromocriptine mesylate0.945 0.84 USP Corn starch NF 9.00 8.00 Granular anhydrous citric acidUSP 1.35 1.20 Anhydrous lactose NF 77.58 69.00 Colloidal silicon dioxideNF 0.45 0.40 Magnesium Stearate NF 0.675 0.60 Total Weight 90.0 80.0

Bulk batches of bromocriptine mesylate were micronized using a jet millunder a nitrogen atmosphere at a controlled temperature of 0° C. Thevolume particle size distribution was measured using a Sympatec HELOSH1013 Laser Diffractometer. The tablets were prepared by geometricalmixing via trituration of micronized bromocriptine mesylate (EuticalsS.p.a., Milan) with corn starch as four triturations in a PKBlendMaster™ V-Blender. Sequentially, two sub-loads of granularanhydrous citric acid and corn starch were mixed in a PK BlendMaster™.These two sub-loads were each divided into two equal sub-loads, yieldinga total of four sub-loads. Each of the four bromocriptine mesylatetriturations was then mixed with adjusted amounts of anhydrous lactose,corn starch and one citric acid/starch corn sub-load in a Fielder PMA 65mixer to form four premixes [A-D]. A 2.0 kg quantity was removed afterPremix A for mixing in a PK BlendMaster™ with colloidal silicon dioxideand magnesium stearate to form a lubricant premix. The four premixeswere then loaded in sequential order, with the lubricant premix loadedin between premixes B and C, into an 8 ft³ in-bin hopper; wherelubrication/final blending is performed. The lubricated blend was thentransferred from the in-bin hopper to a tablet press using a valvedtransfer chute, and then compressed using a 38-station Hata tabletpress.

Example 10 Validation Studies for Tablets Prepared According to Example9

To validate the manufacturing method, three batches were prepared usingsubstantially the method described in Example 9. Batches of micronizedbromocriptine mesylate were obtained from Euticals S.p.a., Milan.

Representative data obtained for tablets prepared from one of thebatches is summarized below.

First, Table 13 summarizes the particle size distribution for themicronized bromocriptine mesylate. The particle size distribution forthis batch is shown in FIG. 5.

TABLE 13 Bromocriptine Mesylate Particle Size Distributions forMicronized Bromocriptine Mesylate used to Manufacture Tablets asDescribed in Example 9. Volume-based Particle Size Distribution % < 1 μm% < 10 μm % < 15 μm 9 98 100

Drug release profiles for samples of the tablets were measured using theUSP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 Nhydrochloric acid at 37° C. Table 14 below shows the drug releaseprofiles obtained for tablets from a representative batch.

TABLE 14 Drug Release from a Representative Batch of BromocriptineMesylate Tablets Prepared as Described in Example 9. Time Average %Release (minutes) (n = 12) 4 18 7 34 10 56 13 76 16 88 19 94 30 98

In addition, blend uniformity and tablet content uniformity wereassessed.

Blend uniformity was assessed by assaying the content of the powderedformulation at twelve locations in the blender following final blendingbut before tableting. The batch met criteria for blend uniformity.

Tablet content uniformity was evaluated by taking samples at 20locations throughout the compression process. Three tablets from eachtime point were then assessed for bromocriptine content. The contentuniformity results obtained are summarized in Table 15.

TABLE 15 Content Uniformity Evaluation for a Representative Batch ofBromocriptine Mesylate Tablets Prepared as Described in Example 9 (n =60 tablets for each batch). Bromocriptine Content (% of label) MeanRange RSD % Pass/Fail 101.4 96.6-103.6 1.2 Pass

Each reference cited in the text of the present application is herebyincorporated by reference in its entirety. A number of embodiments ofthe invention have been described. Nevertheless, it will be understoodthat various modifications may be made without departing from the spiritand scope of the invention. Accordingly, other embodiments are withinthe scope of the following claims.

What is claimed is:
 1. A tablet comprising micronized bromocriptinemesylate and one or more excipients; wherein the micronizedbromocriptine mesylate is present in an amount that provides a dose ofat least about 0.8 mg of bromocriptine per tablet; wherein themicronized bromocriptine mesylate has Dv90 of less than about 10 μm; andwherein the tablet provides a dissolution profile, when tested in USPApparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloricacid at about 37° C., wherein at least about 90% of the bromocriptinemesylate has been released at about 30 minutes.
 2. The tablet accordingto claim 1, wherein the bromocriptine mesylate is present in an amountthat provides a dose of about 0.8 mg of bromocriptine per tablet.
 3. Thetablet according to claim 1, wherein the bromocryptine mesylate has aparticle size distribution with a Dv90 of less than about 5 μm.
 4. Thetablet according to claim 1, wherein the bromocryptine mesylate has aparticle size distribution with a Dv99 of less than about 15 μm.
 5. Thetablet according to claim 1, wherein the bromocryptine mesylate has avolume-based particle size distribution wherein not more than about 20%of the bromocriptine mesylate has a particle size of less than about 1μm.
 6. The tablet according to claim 1, wherein the tablet provides adissolution profile, when tested in USP Apparatus Type 2 Paddle Methodat 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37° C., whereinat least about 95% of the bromocriptine mesylate has been released atabout 30 minutes.
 7. The tablet according to claim 1, wherein the tabletprovides a dissolution profile, when tested in USP Apparatus Type 2Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about37° C., wherein at least about 90% of the bromocriptine mesylate hasbeen released at about 20 minutes.
 8. The tablet according to claim 1,wherein the tablet provides a dissolution profile, when tested in USPApparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloricacid at about 37° C., wherein not more than about 50% of thebromocriptine mesylate has been released at about 7 minutes and not morethan about 75% of the bromocriptine mesylate has been released at about10 minutes.
 9. A method for the manufacture of a bromocriptine mesylatetablet comprising: processing bromocriptine mesylate to reduce theaverage particle size of the bromocriptine mesylate to providebromocriptine mesylate that has a Dv90 of less than about 20 μm;blending the processed bromocriptine mesylate with excipients to form amixture wherein the bromocriptine mesylate is substantially evenlydistributed in the mixture, and compressing the mixture to form atablet; wherein the tablet comprises bromocriptine mesylate in an amountthat provides a dose of at least about 0.8 mg of bromocriptine; andwherein the tablet provides a dissolution profile, when tested in USPApparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloricacid at about 37° C., wherein at least about 90% of the bromocriptinemesylate has been released at about 30 minutes.
 10. The method accordingto claim 9, wherein the bromocriptine mesylate is present in an amountthat provides a dose of about 0.8 mg of bromocriptine per tablet. 11.The method according to claim 9, wherein the bromocriptine mesylate hasDv90 of less than about 10 μm after the processing.
 12. The methodaccording to claim 9, wherein the bromocriptine mesylate has a Dv90 ofless than about 5 μm after the processing.
 13. The method according toclaim 9, wherein the processing comprises micronizing the bromocriptinemesylate.
 14. The method according to claim 9, wherein the tabletprovides a dissolution profile, when tested in USP Apparatus Type 2Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about37° C., wherein at least about 95% of the bromocriptine mesylate hasbeen released at about 30 minutes.
 15. The method according to claim 9,wherein the tablet provides a dissolution profile, when tested in USPApparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloricacid at about 37° C., wherein at least about 90% of the bromocriptinemesylate has been released at about 20 minutes.
 16. The method accordingto claim 9, wherein the tablet provides a dissolution profile, whentested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1N hydrochloric acid at about 37° C., wherein not more than about 50% ofthe bromocriptine mesylate has been released at about 7 minutes and notmore than about 75% of the bromocriptine mesylate has been released atabout 10 minutes.
 17. The method according to claim 9, wherein themixture is transferred from a blending apparatus via a transfer unit toa tableting apparatus for compressing the mixture to form tablets thathave a substantially uniform bromocriptine mesylate content.
 18. Amethod for the manufacture of a bromocriptine mesylate tabletcomprising: determining that bromocriptine mesylate has a particle sizedistribution equivalent to a volume-based particle size distributionwith a Dv90 of less than about 20 μm; blending the bromocriptinemesylate of determined particle size distribution with excipients toform a mixture wherein the bromocriptine mesylate is substantiallyevenly distributed in the mixture, and compressing the mixture to form atablet; wherein the tablet comprises bromocriptine mesylate in an amountthat provides a dose of at least about 0.8 mg of bromocriptine; andwherein the tablet provides a dissolution profile, when tested in USPApparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloricacid at about 37° C., wherein at least about 90% of the bromocriptinemesylate has been released at about 30 minutes.
 19. The method oftreatment for improving glycemic control in a type 2 diabetes patientcomprising administering to the patient a bromocriptine mesylate tabletaccording to claim
 1. 20. A method of treatment for improving glycemiccontrol in a type 2 diabetes patient comprising preparing at least onebromocriptine tablet by a method according to claim 9, and providing thebromocriptine mesylate tablet for administration to the patient.